Abstract 13559: Altered Nucleotide Biosynthesis is a Prominent Metabolic Feature of Cardiac and Liver Aging

Abstract

Introduction: The heart is particularly vulnerable to age-related dysfunction, with left ventricular hypertrophy and diastolic dysfunction developing in late life. In this study, we used deep network tracing to elucidate the effects of aging on glucose metabolism in the heart and peripheral tissues of a mouse model of late-life cardiac dysfunction. Hypothesis: Aging processes in the heart are mediated through altered nucleotide metabolism. Methods: Young (12–16 wk, n =6) and aged (80–84 wk, n =6) male C57BL/6J mice were subjected to treadmill exercise capacity tests and echocardiographic measurements. To delineate the effects of age on in vivo glucose metabolism, we delivered 13 C 6 -glucose to mice via a liquid diet and analyzed 13 C enrichment and the relative abundance of metabolites in the heart, liver, and skeletal muscle by ion exchange chromatography-mass spectrometry. Results: Compared with young mice, aged mice had lower exercise capacity (257.3 vs. 394.2 meters distance, p =0.0002 and 0.9 vs. 1.4 kg/m work, p =0.07), which was associated with a 1.3–fold increase in left ventricular mass ( p =0.0006) and longer isovolumetric relaxation time (IVRT: 12.3 vs. 14.1 ms, p =0.03). Although no significant differences in 13 C enrichment were found for metabolites in the glycolysis and tricarboxylic acid cycle pathways, we found 1.2- to 1.5-fold difference in 13 C enrichment ( p <0.05) in purine (AMP, ADP, ATP and GMP, GDP, GTP) and pyrimidine (UMP, UDP, UTP, uridine, orotidine) metabolites. Additionally, aged hearts had 2.4-fold higher levels of the pyrimidine precursor N-carbamoyl L-aspartate. Similar changes were detected in the pyrimidine metabolite pool in aged liver, but not skeletal muscle. Conclusions: These data indicate that altered nucleotide biosynthesis is a prominent metabolic feature of cardiac and liver aging and could provide novel insights into age-related decrements in cardiovascular health.